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BACKGROUND: Short-term exposure to low and high air temperatures can cause serious harmful effects on human health. Existing literature has mostly focused on associations of ambient air temperature with mortality and the need for health care in population-level studies. Studies that have considered self-perceived health status as an outcome when examining the effects of air temperature on health are scarce. In this study, we explored the short-term association of daily mean air temperature with various measures of self-perceived health status. METHODS: This cross-sectional analysis is based on the Cooperative Health Research in the Region of Augsburg (KORA) FIT study conducted in 2018/2019 and included participants from the Augsburg region of Southern Germany. Health-related quality of life (HRQOL) was evaluated by using the 5-level EuroQol Five Dimension (EQ-5D-5L) questionnaire, including the EuroQol visual analog scale (EQ-VAS). Self-rated health (SRH) and comparative self-rated health (CSRH) were each assessed using a single question. Daily mean air temperature data was estimated using a spatiotemporal model and assigned to participants' home addresses at a resolution of 1 × 1 km. Regression models with a Distributed Lag Non-linear Modeling (DLNM) approach were used to investigate the associations between daily mean air temperature and self-perceived health measures. RESULTS: We found no association of heat or cold with the HRQOL, SRH or CSRH. Nevertheless, there was a significant protective association of low air temperature with the EQ-5D-5L dimension "usual activities." CONCLUSION: There was no evidence of daily mean air temperature adversely affecting participants' self-perceived health status.
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Background: Existing criteria for predicting patient survival from immunotherapy are primarily centered on the PD-L1 status of patients. We tested the hypothesis that noninvasively captured baseline whole-lung radiomics features from CT images, baseline clinical parameters, combined with advanced machine learning approaches, can help to build models of patient survival that compare favorably with PD-L1 status for predicting 'less-than-median-survival risk' in the metastatic NSCLC setting for patients on durvalumab. With a total of 1062 patients, inclusive of model training and validation, this is the largest such study yet. Methods: To ensure a sufficient sample size, we combined data from treatment arms of three metastatic NSCLC studies. About 80% of this data was used for model training, and the remainder was held-out for validation. We first trained two independent models; Model-C trained to predict survival using clinical data; and Model-R trained to predict survival using whole-lung radiomics features. Finally, we created Model-C+R which leveraged both clinical and radiomics features. Results: The classification accuracy (for median survival) of Model-C, Model-R, and Model-C+R was 63%, 55%, and 68% respectively. Sensitivity analysis of survival prediction across different training and validation cohorts showed concordance indices ([95 percentile]) of 0.64 ([0.63, 0.65]), 0.60 ([0.59, 0.60]), and 0.66 ([0.65,0.67]), respectively. We additionally evaluated generalization of these models on a comparable cohort of 144 patients from an independent study, demonstrating classification accuracies of 65%, 62%, and 72% respectively. Conclusion: Machine Learning models combining baseline whole-lung CT radiomic and clinical features may be a useful tool for patient selection in immunotherapy. Further validation through prospective studies is needed.
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Anticorpos Monoclonais , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Tomografia Computadorizada por Raios X , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Masculino , Feminino , Tomografia Computadorizada por Raios X/métodos , Anticorpos Monoclonais/uso terapêutico , Pessoa de Meia-Idade , Idoso , Aprendizado de Máquina , Medição de Risco , Antineoplásicos Imunológicos/uso terapêutico , Prognóstico , Antígeno B7-H1 , RadiômicaRESUMO
Promising evidence suggests a link between environmental factors, particularly air pollution, and diabetes and obesity. However, it is still unclear whether men and women are equally susceptible to environmental exposures. Therefore, we aimed to assess sex-specific long-term effects of environmental exposures on metabolic diseases. We analyzed cross-sectional data from 3,034 participants (53.7% female, aged 53-74 years) from the KORA Fit study (2018/19), a German population-based cohort. Environmental exposures, including annual averages of air pollutants [nitrogen oxides (NO2, NOx), ozone, particulate matter of different diameters (PM10, PMcoarse, PM2.5), PM2.5abs, particle number concentration], air temperature and surrounding greenness, were assessed at participants' residences. We evaluated sex-specific associations of environmental exposures with prevalent diabetes, obesity, body-mass-index (BMI) and waist circumference using logistic or linear regression models with an interaction term for sex, adjusted for age, lifestyle factors and education. Further effect modification, in particular by urbanization, was assessed in sex-stratified analyses. Higher annual averages of air pollution, air temperature and greenness at residence were associated with diabetes prevalence in men (NO2: Odds Ratio (OR) per interquartile range increase in exposure: 1.49 [95% confidence interval (CI): 1.13, 1.95], air temperature: OR: 1.48 [95%-CI: 1.15, 1.90]; greenness: OR: 0.78 [95%-CI: 0.59, 1.01]) but not in women. Conversely, higher levels of air pollution, temperature and lack of greenness were associated with lower obesity prevalence and BMI in women. After including an interaction term for urbanization, only higher greenness was associated with higher BMI in rural women, whereas higher air pollution was associated with higher BMI in urban men. To conclude, we observed sex-specific associations of environmental exposures with metabolic diseases. An additional interaction between environmental exposures and urbanization on obesity suggests a higher susceptibility to air pollution among urban men, and higher susceptibility to greenness among rural women, which needs corroboration in future studies.
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Poluentes Atmosféricos , Diabetes Mellitus , Exposição Ambiental , Obesidade , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Obesidade/epidemiologia , Alemanha/epidemiologia , Exposição Ambiental/efeitos adversos , Diabetes Mellitus/epidemiologia , Estudos Transversais , Poluentes Atmosféricos/análise , Prevalência , Fatores Sexuais , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Material Particulado/análiseAssuntos
Reanimação Cardiopulmonar , Parada Cardíaca , Humanos , Parada Cardíaca/terapia , RessuscitaçãoRESUMO
The lack of readily available methods for estimating high-resolution near-surface relative humidity (RH) and the incapability of weather stations to fully capture the spatiotemporal variability can lead to exposure misclassification in studies of environmental epidemiology. We therefore aimed to predict German-wide 1 × 1 km daily mean RH during 2000-2021. RH observations, longitude and latitude, modelled air temperature, precipitation and wind speed as well as remote sensing information on topographic elevation, vegetation, and the true color band composite were incorporated in a Random Forest (RF) model, in addition to date for capturing the temporal variations of the response-explanatory variables relationship. The model achieved high accuracy (R2 = 0.83) and low errors (Root Mean Square Error (RMSE) of 5.07%, Mean Absolute Percentage Error (MAPE) of 5.19% and Mean Percentage Error (MPE) of - 0.53%), calculated via ten-fold cross-validation. A comparison of our RH predictions with measurements from a dense monitoring network in the city of Augsburg, South Germany confirmed the good performance (R2 ≥ 0.86, RMSE ≤ 5.45%, MAPE ≤ 5.59%, MPE ≤ 3.11%). The model displayed high German-wide RH (22y-average of 79.00%) and high spatial variability across the country, exceeding 12% on yearly averages. Our findings indicate that the proposed RF model is suitable for estimating RH for a whole country in high-resolution and provide a reliable RH dataset for epidemiological analyses and other environmental research purposes.
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Poluentes Atmosféricos , Monitoramento Ambiental , Monitoramento Ambiental/métodos , Umidade , Algoritmo Florestas Aleatórias , Tempo (Meteorologia) , Temperatura , Poluentes Atmosféricos/análiseRESUMO
BACKGROUND: Short-term associations between heat and cardiovascular disease (CVD) mortality have been examined mostly in large cities. However, different vulnerability and exposure levels may contribute to spatial heterogeneity. This study assessed heat effects on CVD mortality and potential vulnerability factors using data from three European countries, including urban and rural settings. METHODS: We collected daily counts of CVD deaths aggregated at the small-area level in Norway (small-area level: municipality), England and Wales (lower super output areas), and Germany (district) during the warm season (May-September) from 1996 to 2018. Daily mean air temperatures estimated by spatial-temporal models were assigned to each small area. Within each country, we applied area-specific Quasi-Poisson regression using distributed lag nonlinear models to examine the heat effects at lag 0-1 days. The area-specific estimates were pooled by random-effects meta-analysis to derive country-specific and overall heat effects. We examined individual- and area-level heat vulnerability factors by subgroup analyses and meta-regression, respectively. RESULTS: We included 2.84 million CVD deaths in analyses. For an increase in temperature from the 75th to the 99th percentile, the pooled relative risk (RR) for CVD mortality was 1.14 (95% CI: 1.03, 1.26), with the country-specific RRs ranging from 1.04 (1.00, 1.09) in Norway to 1.24 (1.23, 1.26) in Germany. Heat effects were stronger among women [RRs (95% CIs) for women and men: 1.18 (1.08, 1.28) vs. 1.12 (1.00, 1.24)]. Greater heat vulnerability was observed in areas with high population density, high degree of urbanization, low green coverage, and high levels of fine particulate matter. CONCLUSION: This study provides evidence for the heat effects on CVD mortality in European countries using high-resolution data from both urban and rural areas. Besides, we identified individual- and area-level heat vulnerability factors. Our findings may facilitate the development of heat-health action plans to increase resilience to climate change.
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Doenças Cardiovasculares , Sistema Cardiovascular , Masculino , Feminino , Humanos , Temperatura Alta , Europa (Continente)/epidemiologia , AlemanhaRESUMO
Increasing evidence has revealed that exposure to low temperatures is linked to a higher risk of chronic diseases and death; however, the mechanisms underlying the observed associations are still poorly understood. We performed a cross-sectional analysis with 1115 participants from the population-based KORA F4 study, which was conducted in Augsburg, Germany, from 2006 to 2008. Seventy-one inflammation-related protein biomarkers were analyzed in serum using proximity extension assay technology. We employed generalized additive models to explore short- and medium-term effects of air temperature on biomarkers of subclinical inflammation at cumulative lags of 0-1 days, 2-6 days, 0-13 days, 0-27 days, and 0-55 days. We found that short- and medium-term exposures to lower air temperature were associated with higher levels in 64 biomarkers of subclinical inflammation, such as Protein S100-A12 (EN-RAGE), Interleukin-6 (IL-6), Interleukin-10 (IL-10), C-C motif chemokine 28 (CCL28), and Neurotrophin-3 (NT-3). More pronounced associations between lower air temperature and higher biomarker of subclinical inflammation were observed among older participants, people with cardiovascular disease or prediabetes/diabetes, and people exposed to higher levels of air pollution (PM2.5, NO2, and O3). Our findings provide intriguing insight into how low air temperature may cause adverse health effects by activating inflammatory pathways.
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Poluentes Atmosféricos , Poluição do Ar , Humanos , Temperatura , Material Particulado/análise , Estudos Transversais , Poluição do Ar/análise , Inflamação/induzido quimicamente , Inflamação/metabolismo , Biomarcadores/análise , Poluentes Atmosféricos/análise , Exposição Ambiental/análiseRESUMO
Climate change poses a serious threat to human health worldwide, while aging populations increase. However, no study has ever investigated the effects of air temperature on epigenetic age acceleration. This study involved 1,725 and 1,877 participants from the population-based KORA F4 (2006-2008) and follow-up FF4 (2013-2014) studies, respectively, conducted in Augsburg, Germany. The difference between epigenetic age and chronological age was referred to as epigenetic age acceleration and reflected by Horvath's epigenetic age acceleration (HorvathAA), Hannum's epigenetic age acceleration (HannumAA), PhenoAge acceleration (PhenoAA), GrimAge acceleration (GrimAA), and Epigenetic Skin and Blood Age acceleration (SkinBloodAA). Daily air temperature was estimated using hybrid spatiotemporal regression-based models. To explore the medium- and long-term effects of air temperature modeled in time and space on epigenetic age acceleration, we applied generalized estimating equations (GEE) with distributed lag non-linear models, and GEE, respectively. We found that high temperature exposure based on the 8-week moving average air temperature (97.5th percentile of temperature compared to median temperature) was associated with increased HorvathAA, HannumAA, GrimAA, and SkinBloodAA: 1.83 (95% CI: 0.29-3.37), 11.71 (95% CI: 8.91-14.50), 2.26 (95% CI: 1.03-3.50), and 5.02 (95% CI: 3.42-6.63) years, respectively. Additionally, we found consistent results with high temperature exposure based on the 4-week moving average air temperature was associated with increased HannumAA, GrimAA, and SkinBloodAA: 9.18 (95% CI: 6.60-11.76), 1.78 (95% CI: 0.66-2.90), and 4.07 (95% CI: 2.56-5.57) years, respectively. For the spatial variation in annual average temperature, a 1 °C increase was associated with an increase in all five measures of epigenetic age acceleration (HorvathAA: 0.41 [95% CI: 0.24-0.57], HannumAA: 2.24 [95% CI: 1.95-2.53], PhenoAA: 0.32 [95% CI: 0.05-0.60], GrimAA: 0.24 [95%: 0.11-0.37], and SkinBloodAA: 1.17 [95% CI: 1.00-1.35] years). In conclusion, our results provide first evidence that medium- and long-term exposures to high air temperature affect increases in epigenetic age acceleration.
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Poluição do Ar , Humanos , Lactente , Poluição do Ar/análise , Temperatura , Material Particulado/análise , Envelhecimento/genética , Epigênese Genética , Metilação de DNARESUMO
PURPOSE OF REVIEW: Acute coronary syndromes represent the commonest cause of out-of-hospital cardiac arrest (OHCA) in adults. Coronary angiography (CAG) followed by percutaneous coronary intervention (PCI) has been established as the treatment strategy for these patients. In this review, we aim first to discuss the potential risks and expected benefits from it, the caveats in its implementation, and the current tools for patient selection. Then summarize the recent evidence on the group of patients without ST-segment elevation on post-return of spontaneous circulation (ROSC) ECG. RECENT FINDINGS: The implementation of this strategy still shows a wide variation among the various systems of care.The presence of ST-segment elevation on post-ROSC ECG remains the most reliable tool for patient selection for immediate CAG.A primary PCI strategy is currently recommended for patients with ST-segment elevation on post-ROSC ECG regardless of the conscious state of patients.Recently several randomised studies including patients without ST-segment elevation on post-ROSC ECG showed no benefit with immediate CAG compared to delayed/ elective CAG. This has led to a substantial although not uniform change in current recommendations. SUMMARY: Recent studies show no benefit with immediate CAG in groups of patients without ST-segment elevation on post-ROSC ECG. Further refinements in selecting the appropriate patients for immediate CAG seem necessary.
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Reanimação Cardiopulmonar , Parada Cardíaca Extra-Hospitalar , Intervenção Coronária Percutânea , Adulto , Humanos , Angiografia Coronária/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Parada Cardíaca Extra-Hospitalar/diagnóstico por imagem , Parada Cardíaca Extra-Hospitalar/terapia , Eletrocardiografia/efeitos adversosRESUMO
AIMS: Quality of care (QoC) is a fundamental tenet of modern healthcare and has become an important assessment tool for healthcare authorities, stakeholders and the public. However, QoC is difficult to measure and quantify because it is a multifactorial and multidimensional concept. Comparison of clinical institutions can be challenging when QoC is estimated solely based on clinical outcomes. Thus, measuring quality through quality indicators (QIs) can provide a foundation for quality assessment and has become widely used in this context. QIs for the evaluation of QoC in acute myocardial infarction are now well-established, but no such indicators exist for the process from resuscitation of cardiac arrest and post-resuscitation care in Europe. METHODS AND RESULTS: The Association of Acute Cardiovascular Care of the European Society Cardiology, the European Resuscitation Council, European Society of Intensive Care Medicine and the European Society for Emergency Medicine, have reflected on the measurement of QoC in cardiac arrest. A set of QIs have been proposed, with the scope to unify and evolve QoC for the management of cardiac arrest across Europe. CONCLUSION: We present here the list of QIs (6 primary QIs and 12 secondary Qis), with descriptions of the methodology used, scientific justification and motives for the choice for each measure with the aim that this set of QIs will enable assessment of the quality of postout-of-hospital cardiac arrest management across Europe.
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Cardiologia , Medicina de Emergência , Parada Cardíaca Extra-Hospitalar , Humanos , Parada Cardíaca Extra-Hospitalar/terapia , Indicadores de Qualidade em Assistência à Saúde , Cuidados CríticosRESUMO
Glucocorticoids prescribed to limit inflammation, have significant adverse effects. As 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) regenerates active glucocorticoid, we investigated whether 11ß-HSD1 inhibition with AZD4017 could mitigate adverse glucocorticoid effects without compromising their anti-inflammatory actions. We conducted a proof-of-concept, randomized, double-blind, placebo-controlled study at Research Unit, Churchill Hospital, Oxford, UK (NCT03111810). 32 healthy male volunteers were randomized to AZD4017 or placebo, alongside prednisolone treatment. Although the primary endpoint of the study (change in glucose disposal during a two-step hyperinsulinemic, normoglycemic clamp) wasn't met, hepatic insulin sensitivity worsened in the placebo-treated but not in the AZD4017-treated group. Protective effects of AZD4017 on markers of lipid metabolism and bone turnover were observed. Night-time blood pressure was higher in the placebo-treated but not in the AZD4017-treated group. Urinary (5aTHF+THF)/THE ratio was lower in the AZD4017-treated but remained the same in the placebo-treated group. Most anti-inflammatory actions of prednisolone persisted with AZD4017 co-treatment. Four adverse events were reported with AZD4017 and no serious adverse events. Here we show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects.
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11-beta-Hidroxiesteroide Desidrogenase Tipo 1 , Anti-Inflamatórios , Prednisolona , Humanos , Masculino , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Anti-Inflamatórios/efeitos adversos , Glucocorticoides/efeitos adversos , Inflamação/tratamento farmacológico , Prednisolona/efeitos adversosRESUMO
AIMS: International guidelines give recommendations for the management of comatose out-of-hospital cardiac arrest (OHCA) survivors. We aimed to investigate adherence to guidelines and disparities in the treatment of OHCA in hospitals in Europe. METHODS AND RESULTS: A web-based, multi-institutional, multinational survey in Europe was conducted using an electronic platform with a predefined questionnaire developed by experts in post-resuscitation care. The survey was disseminated to all members of the societies via email, social media, websites, and newsletters in June 2021. Of 252 answers received, 237 responses from different units were included and 166 (70%) were from cardiac arrest centres. First-line vasopressor used was noradrenaline in 195 (83%) and the first-line inotrope was dobutamine in 148 (64%) of the responses. Echocardiography is available 24/7 in 204 (87%) institutions. Targeted temperature management was used in 160 (75%) institutions for adult comatose survivors of OHCA with an initial shockable rhythm. Invasive or external cooling methods with feedback were used in 72 cardiac arrest centres (44%) and 17 (24%) non-cardiac arrest centres (P < 0.0003). A target temperature between 32 and 34°C was preferred by 46 centres (21%); a target between 34 and 36°C by 103 centres (52%); and <37.5°C by 35 (16%). Multimodal neuroprognostication was poorly implemented and a follow-up at 3 months after discharge was done in 71 (30%) institutions. CONCLUSION: Post-resuscitation care is not well established and varies among centres in European hospitals. Cardiac arrest centres have a higher coherence with guidelines compared with respondents from non-cardiac arrest centres. The overall inconsistency in approaches and deviation from recommendations could be a focus for improvement.
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Reanimação Cardiopulmonar , Medicina de Emergência , Hipotermia Induzida , Parada Cardíaca Extra-Hospitalar , Humanos , Parada Cardíaca Extra-Hospitalar/terapia , Reanimação Cardiopulmonar/métodos , Coma/etiologia , Coma/terapia , Hipotermia Induzida/métodos , Cuidados Críticos/métodos , Inquéritos e Questionários , Europa (Continente)/epidemiologiaRESUMO
The commonly used weather stations cannot fully capture the spatiotemporal variability of near-surface air temperature (Tair), leading to exposure misclassification and biased health effect estimates. We aimed to improve the spatiotemporal coverage of Tair data in Germany by using multi-stage modeling to estimate daily 1 × 1 km minimum (Tmin), mean (Tmean), maximum (Tmax) Tair and diurnal Tair range during 2000-2020. We used weather station Tair observations, satellite-based land surface temperature (LST), elevation, vegetation and various land use predictors. In the first stage, we built a linear mixed model with daily random intercepts and slopes for LST adjusted for several spatial predictors to estimate Tair from cells with both Tair and LST available. In the second stage, we used this model to predict Tair for cells with only LST available. In the third stage, we regressed the second stage predictions against interpolated Tair values to obtain Tair countrywide. All models achieved high accuracy (0.91 ≤ R2 ≤ 0.98) and low errors (1.03 °C ≤ Root Mean Square Error (RMSE) ≤ 2.02 °C). Validation with external data confirmed the good performance, locally, i.e., in Augsburg for all models (0.74 ≤ R2 ≤ 0.99, 0.87 °C ≤ RMSE ≤ 2.05 °C) and countrywide, for the Tmean model (0.71 ≤ R2 ≤ 0.99, 0.79 °C ≤ RMSE ≤ 1.19 °C). Annual Tmean averages ranged from 8.56 °C to 10.42 °C with the years beyond 2016 being constantly hotter than the 21-year average. The spatial variability within Germany exceeded 15 °C annually on average following patterns including mountains, rivers and urbanization. Using a case study, we showed that modeling leads to broader Tair variability representation for exposure assessment of participants in health cohorts. Our results indicate the proposed models as suitable for estimating nationwide Tair at high resolution. Our product is critical for temperature-based epidemiological studies and is also available for other research purposes.
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Temperatura Alta , Urbanização , Humanos , Temperatura , Modelos Lineares , Alemanha , Monitoramento Ambiental/métodosRESUMO
Higher air temperature is associated with increased age-related morbidity and mortality. To date, short-term effects of air temperature on leukocyte telomere length have not been investigated in an adult population. We aimed to examine the short-term associations between air temperature and leukocyte telomere length in an adult population-based setting, including two independent cohorts. This population-based study involved 5864 participants from the KORA F3 (2004-2005) and F4 (2006-2008) cohort studies conducted in Augsburg, Germany. Leukocyte telomere length was assessed by a quantitative PCR-based method. We estimated air temperature at each participant's residential address through a highly resolved spatiotemporal model. We conducted cohort-specific generalized additive models to explore the short-term effects of air temperature on leukocyte telomere length at lags 0-1, 2-6, 0-6, and 0-13 days separately and pooled the estimates by fixed-effects meta-analysis. Our study found that between individuals, an interquartile range (IQR) increase in daily air temperature was associated with shorter leukocyte telomere length at lags 0-1, 2-6, 0-6, and 0-13 days (%change: -2.96 [-4.46; -1.43], -2.79 [-4.49; -1.07], -4.18 [-6.08; -2.25], and -6.69 [-9.04; -4.27], respectively). This meta-analysis of two cohort studies showed that between individuals, higher daily air temperature was associated with shorter leukocyte telomere length.
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Poluição do Ar , Adulto , Humanos , Poluição do Ar/análise , Temperatura , Estudos de Coortes , Leucócitos , TelômeroRESUMO
Background and aims: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition. It is tightly associated with an adverse metabolic phenotype (including obesity and type 2 diabetes) as well as with obstructive sleep apnoea (OSA) of which intermittent hypoxia is a critical component. Hepatic de novo lipogenesis (DNL) is a significant contributor to hepatic lipid content and the pathogenesis of NAFLD and has been proposed as a key pathway to target in the development of pharmacotherapies to treat NAFLD. Our aim is to use experimental models to investigate the impact of hypoxia on hepatic lipid metabolism independent of obesity and metabolic disease. Methods: Human and rodent studies incorporating stable isotopes and hyperinsulinaemic euglycaemic clamp studies were performed to assess the regulation of DNL and broader metabolic phenotype by intermittent hypoxia. Cell-based studies, including pharmacological and genetic manipulation of hypoxia-inducible factors (HIF), were used to examine the underlying mechanisms. Results: Hepatic DNL increased in response to acute intermittent hypoxia in humans, without alteration in glucose production or disposal. These observations were endorsed in a prolonged model of intermittent hypoxia in rodents using stable isotopic assessment of lipid metabolism. Changes in DNL were paralleled by increases in hepatic gene expression of acetyl CoA carboxylase 1 and fatty acid synthase. In human hepatoma cell lines, hypoxia increased both DNL and fatty acid uptake through HIF-1α and -2α dependent mechanisms. Conclusions: These studies provide robust evidence linking intermittent hypoxia and the regulation of DNL in both acute and sustained in vivo models of intermittent hypoxia, providing an important mechanistic link between hypoxia and NAFLD.
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Steroid 5ß-reductase (AKR1D1) plays important role in hepatic bile acid synthesis and glucocorticoid clearance. Bile acids and glucocorticoids are potent metabolic regulators, but whether AKR1D1 controls metabolic phenotype in vivo is unknown. Akr1d1-/- mice were generated on a C57BL/6 background. Liquid chromatography/mass spectrometry, metabolomic and transcriptomic approaches were used to determine effects on glucocorticoid and bile acid homeostasis. Metabolic phenotypes including body weight and composition, lipid homeostasis, glucose tolerance and insulin tolerance were evaluated. Molecular changes were assessed by RNA-Seq and Western blotting. Male Akr1d1-/- mice were challenged with a high fat diet (60% kcal from fat) for 20 weeks. Akr1d1-/- mice had a sex-specific metabolic phenotype. At 30 weeks of age, male, but not female, Akr1d1-/- mice were more insulin tolerant and had reduced lipid accumulation in the liver and adipose tissue yet had hypertriglyceridemia and increased intramuscular triacylglycerol. This phenotype was associated with sexually dimorphic changes in bile acid metabolism and composition but without overt effects on circulating glucocorticoid levels or glucocorticoid-regulated gene expression in the liver. Male Akr1d1-/- mice were not protected against diet-induced obesity and insulin resistance. In conclusion, this study shows that AKR1D1 controls bile acid homeostasis in vivo and that altering its activity can affect insulin tolerance and lipid homeostasis in a sex-dependent manner.
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Glucocorticoides , Oxirredutases , Animais , Ácidos e Sais Biliares , Dieta Hiperlipídica , Feminino , Glucocorticoides/metabolismo , Insulina/metabolismo , Lipídeos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredutases/genética , FenótipoRESUMO
The aim of these guidelines is to provide evidencebased guidance for temperature control in adults who are comatose after resuscitation from either in-hospital or out-of-hospital cardiac arrest, regardless of the underlying cardiac rhythm. These guidelines replace the recommendations on temperature management after cardiac arrest included in the 2021 post-resuscitation care guidelines co-issued by the European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM). The guideline panel included thirteen international clinical experts who authored the 2021 ERC-ESICM guidelines and two methodologists who participated in the evidence review completed on behalf of the International Liaison Committee on Resuscitation (ILCOR) of whom ERC is a member society. We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and grade recommendations. The panel provided suggestions on guideline implementation and identified priorities for future research. The certainty of evidence ranged from moderate to low. In patients who remain comatose after cardiac arrest, we recommend continuous monitoring of core temperature and actively preventing fever (defined as a temperatureâ¯>â¯37.7⯰C) for at least 72 hours. There was insufficient evidence to recommend for or against temperature control at 32-36⯰C or early cooling after cardiac arrest. We recommend not actively rewarming comatose patients with mild hypothermia after return of spontaneous circulation (ROSC) to achieve normothermia. We recommend not using prehospital cooling with rapid infusion of large volumes of cold intravenous fluids immediately after ROSC.
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Reanimação Cardiopulmonar , Hipotermia Induzida , Parada Cardíaca Extra-Hospitalar , Adulto , Cuidados Críticos , Humanos , Parada Cardíaca Extra-Hospitalar/terapia , Ressuscitação , TemperaturaRESUMO
The aim of these guidelines is to provide evidencebased guidance for temperature control in adults who are comatose after resuscitation from either in-hospital or out-of-hospital cardiac arrest, regardless of the underlying cardiac rhythm. These guidelines replace the recommendations on temperature management after cardiac arrest included in the 2021 post-resuscitation care guidelines co-issued by the European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM). The guideline panel included thirteen international clinical experts who authored the 2021 ERC-ESICM guidelines and two methodologists who participated in the evidence review completed on behalf of the International Liaison Committee on Resuscitation (ILCOR) of whom ERC is a member society. We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and grade recommendations. The panel provided suggestions on guideline implementation and identified priorities for future research. The certainty of evidence ranged from moderate to low. In patients who remain comatose after cardiac arrest, we recommend continuous monitoring of core temperature and actively preventing fever (defined as a temperature > 37.7 °C) for at least 72 h. There was insufficient evidence to recommend for or against temperature control at 32-36 °C or early cooling after cardiac arrest. We recommend not actively rewarming comatose patients with mild hypothermia after return of spontaneous circulation (ROSC) to achieve normothermia. We recommend not using prehospital cooling with rapid infusion of large volumes of cold intravenous fluids immediately after ROSC.